Benfotiamine has previously been disclosed in patent US19623064000. Its full name is S-benzoylthiamine O-monophosphate, generic name is benfotiamine, chemical name is Benzenecarbothioic acid, chemical name of formula is S-[2-[[(4-amino-2-methyl-5 pyrimidinyl)methyl]formylamino]-1-[2-(phosphonooxy)ethyl]-1-propenyl]ester, the formula is C19H23N4O6PS and molecular weight is 466.45. It has the following chemical structural:

A substance with the same chemical composition may crystallize with two or more different spatial lattice arrangements. This phenomenon is called polymorphism. The polymorphic behavior of drugs can be of crucial importance in pharmacy and pharmacology, which takes tremendous impacts on drug quality. Varied crystalline forms may differ from each other with respect to one or more physical properties, such as crystal shape, melting point, hardness, solubility and dissociation, state stability and compaction behavior. The differences in physical properties exhibited by polymorphs affect pharmaceutical parameters such as storage stability, bioavailability and efficacy. Therefore, new drug R&D should give more attention to the research on drug polymorphism and crystalline control.
Benfotiamine is the fat-soluble derivative of vitamin B1, which greatly improve low-bioavailability of water-soluble vitamin B1, elevating thiamine level in blood and tissues, so as to its therapeutic efficacy. Indications for benfotiamine: (1) prevention and treatment of vitamin B1 deficiency; (2) additional supplement for vitamin B1 inadequacy from diet malabsorption (due to fatigue, hyperthyroidism, pregnancy, lactation, intensive physical labor); (3) wernicke's encephalopathy; (4) beriberi; (5) any other diseases result from vitamin B1 deficiency and disorders, such as neuropathy, muscle pains, joint pains, peripheral polyneuritis, peripheral nerve paralysis, myocardial metabolic disorder, constipation and other gastrointestinal dysfunction. Benfotiamine has been industrialized and distributed in America, Japan, Europe and other countries as vitamin B1 supplements. Recent study demonstrates that benfotiamine also exhibits notable beneficial effect on diabetes peripheral neuropathy and retinopathy. Additionally, our study also illustrates that benfotiamine is useful in preventing and treating Alzheimer's disease (AD) and aging.
AD is an aging-related progressive neurodegenerative disease, of which the most common early symptoms are cognitive and behavior impairments. The incidence of AD increases dramatically with the ageing of the society. There were 6 million people in China with AD. AD is predicted to affect 30 million individuals globally by 2050. The death rates of cancers, stroke, and cardiovascular diseases as the leading cause of the death decrease according to the progress of medical therapy, but AD incidence is still roaring in large percentage. Additionally, due to long-lasting and high impairment rate of AD, it has turned into one of the most severe life-threatening diseases in 21st century. The medical treatment costs of AD have been calculated to 604 billion US dollars in 2010, which account for almost 1% of global GDP.
As of nowadays, including China and America, two categories of drugs have been approved for AD treatment: acetylcholinesterase inhibitors and N-methyl-D-asparate receptor antagonist. However, no medication has been clearly shown to delay or halt the progression of the disease. Benfotiamine has been proved to reduce celebral β-amyloid (Aβ) deposition and tau hyperphosphorylation, subsequently alleviating the AD pathologic occurrence.
Benfotiamine is mainly administered by tablets and powders, but rarely disclosing the exact crystalline forms involved in these drugs. No systematic researches have been carried out in crystalline polymorphs of benfotiamine. The present invention is related to a systematic insight of crystalline polymorphs of benfotiamine. The characters of diverse crystalline forms of benfotiamine and their potential for new drug development are disclosed.
Three documents have been found to be the most closely related to the present invention on the basis of technical features:
D1: JP  37-13484B (Sankyo company, Ltd.)(Oct. 9, 1962), discloses a colorless needle-like purified benfotiamine crystal, with a melting point of about 160° C.-162° C.
D2: JP  37-16042B (Sankyo company Ltd.)(Aug. 10, 1962), discloses three benfotiamine crystalline forms, comprising crystalline form α (C19H23O6N4SP.2H2O, melting point about 165° C.), crystalline form β (C19H23O6N4SP.15H2O, melting point about 150° C.), and crystalline form δ (C19H23O6N4SP, melting point about 195° C.).D3: B1(6) S-Benzoylthiamine O-Monophosphate  1962, 14 , 64-66, ISSN: 0371-8670, discloses benfotiamine crystalline form δ and its hydrates.
D2 discloses a method for making benfotiamine crystalline form α by keeping temperature 0-5° C. and adjusting pH to 4, which is theoretically identical to the process of preparing benfotiamine crystalline form disclosed in example 1 of D1. We further confirm that benfotiamine crystalline form in D1 and benfotiamine crystalline form α in D2 are the same through their melting point. The hydrates crystalline forms of benfotiamine disclosed in D3 are equivalent to crystalline form α and γ in D2. D2 and D3 disclose a benfotiamine crystalline form δ without crystal water, of which the melting point is 195° C.